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| United States Patent |
5,786,385
|
|
Gorinsky
|
July 28, 1998
|
Polyacetylenes
Abstract
A 2-(1-nonen-3,5,7-triynyl)3-hydroxy tetrahydropyran (cunaniol)
particularly that having the formula:
##STR1##
or a corresponding anhydrocunaniol or cunanione, for use in therapy,
especially as a reversible heart blocking agent or neuromuscular active or
in neurofunction generally; or for use as a pesticide or mycobactericide.
| Inventors:
|
Gorinsky; Conrad (The Old House, Old House Lane, Nazeing, GB2)
|
| Appl. No.:
|
644894 |
| Filed:
|
May 10, 1996 |
Foreign Application Priority Data
| Current U.S. Class: |
514/460; 549/416; 549/420 |
| Intern'l Class: |
A61K 031/40; C07D 315/00 |
| Field of Search: |
514/460
549/416,420
|
References Cited
Other References
Chemische Berichte, vol. 108, No. 2, 1975, Weinheim De pp. 437-439 F.
Bohlmann "ein Neues Sesquiterpenlacton aus Matricaria suffructicosa Var.
Leptoloba".
Chemische Berichte vol. 107, No. 2, 1974, Weinheim De pp. 654-656 Bohlmann
"Synthese Des Ichthiotherol-Acetats".
Chemical Abstracts, vol. 97, No. 11, 1982, Abstract No. 3501c Bohlmann et
al "Naturally Occuring Terpene Derivatives. Part 379"p. 355 col. 1.
Chemical Abstracts, vol. 80, No. 11, 1974, abstract No. 12513j, Gorinsky et
al "Isolation of Ichthiothereol and its Acatate from Clibadium Sylvestre"
p. 223. col. 1.
|
Primary Examiner: Higel; Floyd D.
Attorney, Agent or Firm: Nixon & Vanderhye
Parent Case Text
This application is a continuation-in-part of application of Ser. No.
08/434,116,filed 2 May 1995, now abandoned, which is a continuation of
application Ser. No. 08/189,682, filed 1 Feb. 1994 , now abandoned.
Claims
I claim:
1. A method of treatment of a person affected by a disease or condition
benefited by administration of a reversible heart blocking agent, a
neuromuscular active or a neuroactive generally, said neuromuscular active
being a drug which acts on myoneural junctions, and said neuroactive being
a drug that provides benefits in conditions that affect neurofunction,
wherein an effective amount of a cunaniol
(2-(1-nonen-3,5,7-triynyl)-3-hydroxytetrahydropyran) of formula I, an
anhydrocunaniol of formula II or III or cunanione of formula IV, as set
out below, is administered as said agent or active,
##STR5##
wherein R=H, alkyl, acyl or glycosidyl.
2. The method of treatment according to claim 1, wherein the cunaniol,
anhydrocunaniol or cunanione is in the form of a derivative obtained by
substitution or hydrogenation or both or by glycosidylation.
3. The method of treatment according to claim 2, wherein the derivative is
obtained by substitution at the hydroxy group by etherification with an
alkyl or an n-6 or n-3 essential fatty alcohol group.
4. The method of treatment according to claim 3, wherein the alkyl is
methyl.
5. The method of treatment according to claim 2, wherein the derivative is
obtained by esterification with an acyl.
6. The method of treatment according to claim 5, wherein the acyl is an n-6
or n-3 essential fatty acyl group.
Description
The invention relates to polyacetylene derivatives, and especially to the
tetrahydro pyranol derivatives known as cunaniols, and their derivatives.
The term "cunani" has long been used by Amerindians for a group of fast
acting fish poisons. Such fish poisons are generally derived from plants,
and especially from the leaves thereof. South America probably possesses
greater numbers of recorded fish poison plants than any other continent.
For example, Guyana is thought to have about 40 such fish poison plants.
Effective fish poisons may be derived from the root of the Kurukuruwai
plant, or from the sap, leaves or stems of the Kumarau plant. The fruit of
the Sisal plant may be crushed in water and used as a fish poison.
The present invention however is concerned with a particular class of
compounds which are polyacetylenes as set out in the claims herein, and
their derivatives. These polyacetylenes include cunaniols of the following
general formula I:
##STR2##
wherein R is H, alkyl (especially methyl), acyl or glycosidyl. The
invention further embraces the corresponding anhydrocunaniols and
cunanione and derivatives arising by hydrogenation of the hydrocarbon
chain.
The structures of the anhydrocunaniols correspond to the dehydration
products of cunaniol (R=H) above i.e. removal of the OH group at the
3-position of the ring together with the removal of a hydrogen atom at
either adjacent carbon. These structures are shown as formulae II and III
below.
##STR3##
The structure of cunanione corresponds to the removal of the RO and H
groups of formula I above to give a carbonyl group at the 3-position of
the ring, as shown in formula IV below.
##STR4##
The synthesis of the anhydrocunaniols and cunanione from cunaniol can, of
course, be readily achieved using standard chemical procedures known to
those skilled in the art.
The above compounds may be isolated from leaves of the plant Clibadium
sylvestre (Aubl.) Baill., which is a member of the family Compositae,
trans cunaniol being the most abundant. It has long been recognised that
the crushed leaves of this plant in water cause fish to surface and jump
out of the water. Death results from the poison following paralysis. Gill
action appears to be maintained to the end. Cunani is used as a general
fish poison, but is also mixed with some starch and made into small balls
which are fed to fish, which become disorientated on eating it and are
easily caught by hand.
In the isolation of cunaniols, extracts of leaves from Clibadium sylvestre
(Aubl.) Baill. may be prepared using refluxed petroleum 60/180, or in a
cold extraction process with petrol 60/80, or in a mass extraction process
using ethanol. The extract of cunani leaves may be further refined using a
Quickfit and Quartz (Stone, Staffordshire, UK) steady state counter
current distribution machine (SSDM). The lower phase fractions from the
SSDM may then be collected and concentrated. This extract may then be
further purified, for example, by column chromatography, to obtain
cunaniol acetate.
The lower phase concentrate from the SSDM may be extracted e.g. with
n-hexane, and submitted to column chromatography to obtain trans-cunaniol.
Cunaniol acetate can be isolated directly from the leaves of the cunani
plant, or cunaniol can be derivatised to provide cunaniol acetate. The
anhydrocunaniol and cunanione can also be isolated from the leaves of the
cunani plant.
As noted above the invention embraces derivatives of cunaniol, such as the
alkyl, acyl or glycosidyl derivatives. Examples of suitable derivatives
include derivatives of essential fatty acids such as gamma-linolenic acid
or dihomo-gamma-linolenic acid or others of the twelve n-6 and n-3
essential fatty acids, which are novel compounds and an aspect of the
invention in themselves whether based on the fatty acids as such or in the
corresponding fatty alcohols.
Hydrogenation where desired is carried out by standard catalytic
hydrogenation methods to give fully or partly hydrogenated derivatives.
The cunaniol molecule and its related molecules are lipophilic, due to the
presence of the polyacetylene chain. The molecules can therefore perturb
cell membrane function. Crude extracts of the cunani plant are known to be
very effective and extremely quick-acting fish poisons, the active agent
in the cunani fish poison being cunaniol or its derivatives.
PHYSIOLOGICAL PROPERTIES
CNS Stimulant
Cunaniol is about ten times as active and ten times as rapid as the classic
central nervous system stimulant picrotoxin. Convulsant action can be
antagonised by prior exposure to anticonvulsants such as phenobarbitone or
troxidone. In structure-activity relationship studies it was found that
the highly unsaturated side chain was essential for convulsant activity.
When administered to frogs by injection or by topical application cunaniol
causes clonic convulsions and death (intraperitoneal injection LD50 is
12.8 mg/kg). The effects of cunaniol on frog spinal cord preparation
resemble those of nicotine.
Cunaniol has been shown to be a clonic convulsant when administered
intraperitoneally or orally into mice. The convulsant actions of cunaniol
were mimicked closely by leptazol, and less closely by picrotoxin, but
differed from the tonic convulsions produced by strychnine. Cunaniol was
the most potent of the clonic convulsants by both routes of
administration, and its effects usually occurred more rapidly than with
the other compounds. In comparison, rotenone (a metabolic toxin) for
example, was highly toxic to mice but its effects were qualitatively
different from the convulsants. Rats are also sensitive to the convulsant
actions of cunaniol, a convulsant dose being 5 mg/kg. A dosage of 2.24
mg/kg is a non-convulsant dose while 10 mg/kg causes death
(intraperitoneal injection).
The effects of cunaniol on pentobarbitone sodium induced sleep in rats were
compared with those of the analeptic bemegride. 5 mg/kg of cunaniol
administered by intraperitoneal injection antagonises pentobarbitone while
7.4 mg/kg reduces "sleeping time" by 50% after intraperitoneal
administration of a concentration of 40 mg/kg pentobarbitone sodium. In
this respect cunaniol proved more potent than bemegride (45.7 mg/kg for a
50% reduction of "sleeping time").
Thus, cunaniol demonstrates advantages over bemegride and leptazol as an
analeptic and may prove to be of value as an antagonist in the treatment
of barbiturate-induced central depression and suggests a more selective
anti-phenobarbitone action.
Cunaniol is a GABA (gamma-amino-butyric acid) antagonist, and thus an
important probe for the GABAergic system.
Cardiac Properties and other effects on the Cardiovascular System
Cunaniol exhibits a dual action on the cardiovascular system, comprising a
transient depressant effect on the heart and a sustained pressor response,
probably centrally mediated.
Preliminary experiments on the isolated rabbit heart demonstrated that
perfusion with high cunaniol concentrations (100 .mu.g/ml) results in a
negative inotropic effect culminating in complete but reversible cardiac
arrest in diastole. A similar experiment with rotenone did not exhibit the
reversibility.
Small doses of cunaniol reduce contractability of the rat heart, whereas
larger doses cause complete heart block. This is rapidly reversed on
washing out and with no apparent impairment of function.
In intact anaesthetised rats, a sustained pressor response is produced by
cunaniol administered by intravenous injection in doses of 0.5 mg or
greater. In pithed rats the response to cunaniol was abolished, indicating
a central action of the polyacetylene.
Neuro-Muscular Action
Experiments have been carried out on frog and rat isolated striated muscle
preparations. It was found that cunaniol causes an increased response to
nerve stimulation, followed at higher concentrations by a failure in
neuromuscular transmission.
The effects of cunaniol on the isolated rat phrenic nerve-diaphragm
preparation are characterised by a marked potentiation by direct action on
the muscle at concentrations as low as 12.5 .mu.g/ml, this effect being
dose dependent, followed by complete neuromuscular block at higher
concentrations (100 .mu.g/ml). This is not reversed by neostigmine, i.e.
is not curare-like. The block is readily reversed by washing but the
potentiation is more slowly (60 mins) removed.
APPLICATIONS
Applications may therefore include use as a rapidly reversible local
anaesthetic or as a cardiac membrane stabiliser, and generally as a
reversible heart blocking or heart recovery agent or as a neuromuscular
active (i.e. a drug that acts on myoneural junctions) or as a neuroactive
in neurofunction broadly (i.e. as a drug that has activity and provides
benefits in conditions that affect neurofunction). As stated above,
cunaniol may also be of use as an analeptic. Other applications may
include use as a muscle stimulant. The lipophilic nature of the compounds
enables them to pass the blood-brain barrier, an effect enhanced by
essential fatty acid derivatisation.
Furthermore, the neurotoxic properties may be made use of in pesticides
against insects or any other pest having vulnerable neurofunction, by
application to the pest or to a substrate affected by or to be protected
from the pest. The structure of the compounds also indicates use as a
mycobactericide, mycomycin being a tri-yne mono-ene antibiotic.
Cunaniol or its derivatives may also be used as an effective toxin. When
tested on guppies at approximately 10.sup.-6 M the poison gives rise to
restless movement after two minutes, wild swimming, convulsion and coma
with the body bent laterally after ten minutes. If the fish are removed
into fresh water at this stage, they recover completely in approximately
twenty minutes and show no subsequent symptoms. Fish treated in this way
are found to be edible almost immediately. Phenobarbitone readily
antagonises all responses of guppies to cunaniol. Cunaniol is highly
effective in the release of fry from viviparous fish, due to its effects
on neuromuscular function.
The invention is further illustrated by the following examples:
SYNTHETIC EXAMPLES
Example 1
Dried cunani leaves (8 Kg) were hand-crushed and loosely packed into a
Q.V.F. extraction vessel which was then filled with petrol 60/80 using a
Quickfit glass centrifugal pump and left for one week. The petrol extract
(60 liters) was evaporated down to a syrup (190 g) on a climbing film
evaporator and subsequently on a water bath.
The Quickfit and Quartz steady state counter current distribution machine
(SSDM) was used in the isolation procedure and in the analysis of the
crude extracts.
Solvent Preparation
The solvents, methanol (Burroughs A.R. grade) 3,600 mls, Petroleum ether
60/80 (redistilled) 4,000 mls and water (deionised) 400 mls. were mixed in
an aspirator (10 1), covered and stirred vigorously for about one hour
yielding a syrup (152 g.). This indicates a separation of about 90% of the
crude material into upper phase. The portion of the SSDM train represented
by tubes -10 to -52 --constitutes the main fraction of interest. On
evaporation to low volume on a water bath, this fraction yielded large
quantities of fibrous greenish yellow crystalline material, which has low
solubility in water, and a melting point of from 82.degree. to 84.degree.
C. When recrystallised from n-hexane the material had a melting point of
from 86.degree. to 87.degree. C. Analysis: Calculated for C.sub.14
H.sub.14 O.sub.2 : C78.5, H 6.6%; Found, C 78.77, H 6.41%.
SSDM
The steady state distribution program was based on Counter Current
Distribution as described in Technique of Organic Chemistry (Ed. A.
Weissberger, 3, Part 1, Publ. Interscience, 149-332 (1956)).
Crude syrup (190 g.) from the cold petrol extraction was dissolved in upper
phase solvent (150 mls.). A steady state distribution program was used,
based on a Kp value for cunaniol acetate of 0.54 obtained previously from
Craig Distribution studies. The mixture was then loaded into the SSDM
dosage pump.
The program selecter was set for the sequence (UL).sup.3 (U).sup.3
L(U).sup.2 (ULUI).sup.5 (UL)2. This was derived from a Y/X program of 11
lower phase transferred to 20 upper phase transfers which would retain the
cunaniol acetate at tube 0 in the centre of the SSDM train.
The agitation and settle timers were both set at 45 seconds and a feed
program of 1 ml./transfer for the duration of 24 transfers, when the
feeding program was altered to 0.8 ml./transfer. The feeding program was
terminated after 464 transfers and an analysis of the train was made after
620 transfers. Cunaniol acetate was concentrated in the centre of the
machine.
It appeared that prolonged heating of petroleum extracts in the initial
extraction operations reduced the yield of cunaniol acetate which could
best be extracted from the leaves by cold percolation with solvent. The
acetate was shown to be easily hydrolysed with sodium bicarbonate.
The upper phase fractions coming out of the machine were discarded. The
lower phase fractions coming out of the SSDM were collected in
approximately 1 liter fractions. Feeding was stopped after 464 transfers
are completed and a further 280 cycles were set to sweep out the machine.
The last lower phase bulk fraction (1 liter) was set aside from the other
lower phase fractions which were previously separately collected (5
liters). This lower phase sample was evaporated to an aqueous residue
which was then extracted with ether. The ether was removed and the syrup
was refluxed with n-hexane (100 ml.) and the supernatant decanted.
A colourless oil was deposited from the n-hexane solution which decomposed
to a dark brown oil if left exposed to air and light. This oil exhibited a
strong cunaniol-type, 4-banded U.V. spectrum as well as a similar Rf. on
T.L.C. and was generally referred to as `pre-cunaniol oil`. The mass
spectrum of this oil indicated the presence of molecular ions of mass 214
with fragments characteristic of cunaniol. A second molecular ion peak at
m/e 228 indicated the possibility of cunaniol methyl ether. Further
investigation of this oil indicated the presence of cis-cunaniol, which
has only about 1/60th of the potency of the trans form but may in some
applications be valuable for that reason.
The contents of the train tubes 0 to +30 appearred pale yellow in colour
whereas the contents in tubes on the lower bank appeared green in colour.
The contents of tubes 0 to +30 and -1 to -52 were evaporated down
separately to low bulk, extracted with ether, dried over anhydrous sodium
sulphate and concentrated. TLC indicated the presence of cunaniol acetate
but no cunaniol.
Purification of cunaniol acetate
A further purification of cunaniol acetate was effected by column
chromatography using silica gel eluted with Petrol/benzene. A colourless
sample was obtained in a fraction of about 1 liter of benzene which
yielded a yellow oil on evaporation. Crystalline cunaniol acetate was
easily obtained from ethanol, m.p. 66.5.degree.-67.5.degree. C. Analysis:
Calculated for C.sub.16 H.sub.16 O.sub.3, C 75.0, H 6.3%; Found, C 74.96,
H 6.38%.
Column Chromatography of the n-hexane extract
The sample was prepared from the 2nd n-hexane extraction of the lower phase
concentrate from the SSDM, the extract being reduced to a syrup which is
dissolved in a minimum amount of petrol 60/80.
A column (1 cm.times.40 cm) fitted with a sinter was packed with silica
gel, Merck SG 31 (25 g.) as a slurry in benzene and then equilibrated with
the eluting solvent (1% dry enthanol in petrol 60/80). The sample (190
mg.) was put on the column dissolved in petrol (2 ml.) and the elution
(flow rate 2 mls./min) was monitored by U.V. (234 m.mu..) and optical
rotation. An LKB chopper bar multichannel chart recorder was used to plot
the changes in U.V., optical rotation and fraction change.
Three main fractions were resolved, after which time a gradient elution was
carried out by increasing the concentration of ethanol until the column
was stripped with pure ethanol. The second fraction yielded cunaniol which
crystallised readily on evaporation of the solvent to low volume.
Some samples appearred to be more strongly adbsorbed on the silica gel and
4% ethanol was required for the elution of the fractions.
However, a separation could be effected in all cases and the second main
component from the column appearred to contain cunaniol-type compounds
from the U.V. and TLC evidence. Rechromatography of the cunaniol fraction
under the same column conditions and monitored on a continuous recording
polarimeter indicated two fractions with opposite rotations, the slower
running fraction having a positive rotation and the faster running
fraction a negative rotation. The latter crystallised from the
ethanol-petrol eluate giving a crude m.p. 70.degree.-80.degree. C. and TLC
and mass spectrum indicating that cunaniol is the only component.
Isolation of trans-cunaniol
The final purification of trans-cunaniol was best effected by
recrystallisation of crude cunaniol material from n-hexane which was then
decanted off any residual syrup and left to recrystallise in a
refrigerator. In some fractions a colourless oil was deposited before
cunaniol crystallised and in some samples no crystalline cunaniol appeared
at all, but the cunaniol-type 4 banded U.V. spectrum was still exhibited.
The oily component was referred to as "pre-cunaniol oil". On subsequent
analysis these oil fractions were found to yield cunaniol and also two
other principal polyacetylenes, hydroxy-tetrahydrocunaniol and
contaminating cis-cunaniol.
Purification of a cunaniol containing fraction was achieved by column
chromatography using dry benzene on a silica gel column.
Cunaniol crystallised white clusters of fine needles from n-hexane and the
solid readily decomposed to a brown material on prolonged exposure to
light and air. The pure material possessed a characteristic sickly sweet
smell and could be kept for years in the solid state under n-hexane in the
dark and in a refrigerator.
Physical properties of trans-cunaniol
Molecular weight 214, C.sub.14 H.sub.14 O.sub.2. Fine white needles from
n-hexane, m.p. 90.degree. C. unstable to oxygen and light.
›a!.sub.D (0.3, in CHCl.sub.3)=-40
U.V. spectrum: Typical 4 banded 1.sub.max at 330, 309, 290, 273 nm, mol.
absorption coefficient approx 10,000 for each.
Infra-red spectrum: 950 cm.sup.-1 (trans double bond), 3620 cm.sup.-1
(hydroxyl), 2220 cm.sup.-1 (acetylene)
N.M.R. spectrum: d 1.98 (CH.sub.3 --C=.tbd.C--) d6.29, 5.80 (vinyl protons
- 16 cps - trans coupling)
Mass spectrum: Leading ion 214, Principle fragments at 71,100, 115 and 143
Properties of cis-cunaniol
Melting point, crystallised from ethanol 100.degree.-102.degree.
›.alpha.!D+37.5 (0.3% in chloroform)
I.R. spectrum
740 cm.sup.-1 (cis double band, no evidence of trans)
3600 cm.sup.-1 (hydroxy)
2200 cm.sup.-1 (acetylene)
N.M.R. in deuterochloroform
4.2, 3.9 (vinyl) protons; coupling Jab 10 cycles Jae 8 cycles
from spin decoupling experiments; ABX splitting which appears
in this region consistent with cis configuration
Example 2
The acetyl derivative of cunaniol was prepared in the following manner.
Cunaniol (146 mg) was dissolved in redistilled acetic anhydride (1.5 mls)
to which pyridine (5 drops) was added. The reaction mixture was left in
the freezing compartment of a refrigerator, under nitrogen and in the
dark. Ten days later the reaction mixture was dissolved in ether (25 mls)
which gave a yellow solution. The mixture was extracted with 1 N
hydrochloric acid (15 mls) in three portions followed by washing with
water (10 mls) in two portions. The mixture was then treated with portions
of a saturated solution of sodium bicarbonate (10 mls) until there was no
effervescence on shaking. The ether was dried over sodium sulphate (2 g)
filtered, and evaporated down to a pale yellow syrup (290 mg) on a water
bath and under reduced pressure. The syrup was slightly warmed and
evacuated by an oil pump connected through a solid CO.sub.2 /acetone cold
trap. The condensate in the cold trap appeared to be acetic acid. The
syrup was then extracted with n-hexane (5 mls) to which dry methanol (2
mls) was added and left in a freezing compartment. Large prismatic
crystals appeared, which melted, m.p 61.degree.-62.degree. C. to a pale
yellow oil with no sign of decomposition.
In another experiment the reaction product, after being dissolved in carbon
tetrachloride for N.M.R. measurements, was taken up in a small amount of
methanol and white fibrous crystals appeared when placed in the freezer.
The fibrous crystals were found to turn voilet on evaporation of the
solvent. The crystals melted, m.p. 65.5 -67.50.degree. C., first to a
transparent melt with violet coloured fibres embedded in it. The fibres
darkened at about 150.degree. C. and darkened the previously transparent
melt. The scale-expanded infra red spectrum of the semi-synthetic cunaniol
acetate was exactly superimposable on the spectrum obtained from cunaniol
acetate isolated from the leaves.
Essential fatty acid esters are prepared by like methods and, generally,
derivatision including for example with fatty acid alcohols is by methods
known in themselves.
Example 3
Cunaniol was glycosidated. The reagent used in the glycosidation was
2,3,4,6-tetra-O-acetyl-d-glucal, which was prepared from
2,3,4,6-tetra-0-acetyl-d-glucosyl bromide. A method was adopted using the
glucal with BF.sub.3 as a catalyst to produce the corresponding
2,3-unsaturated glucopyranoside.
D-Glucose (100 g) was used to prepare the acetobromoglucose (186 g), m.p.
85.degree.-86.degree. C. This was converted to the glucal (syrup, 140 g)
which crystallised from petrol 60/80 chloroform solvent, m.p.
52.degree.-530.degree. C., ›a!D.sup.22 -13.5, C, 2.3 in ethanol.
Cunaniol (120 mgs) was dissolved in sodium dried benzene (10 ml) and boron
trifluoride etherate (0.2 mls) was added to the solution which darkened in
colour.
Glucal (186 mgs) dissolved in sodium-dried benzene (5 mls) was added
dropwise and the mixture left overnight at room temperature. The following
day the solution had turned a very dark colour and anhydrous sodium
carbonate (approx. 500 mgs) was added and the reaction mixture was
filtered.
The benzene solution was added to a column (1.times.25 m) packed with
silica gel, Whatman Chromedia SG31 (30 g) and equilibrated with benzene. A
gradient elution was carried out with benzene (sodium
dried)/chloroform/ethanol as the eluting solvents. Four well resolved
fractions were obtained. The eluate was monitored at 333 mm.
The results are presented in Table I. Approximately 56% reaction occurred
with the formation of the glycoside with a trace of the cunaniol acetate
formed as a side reaction. The glycosidic fraction was not analysed.
TABLE 1
______________________________________
Column chromatography of cunaniol-glycoside reaction mixture
Fraction
Eluent Observation Yield
______________________________________
1 .O slashed.H, 200 mls
Colourless 5 mgs.
cunaniol-type U.V.
mol. wt. 256; (cunaniol acetate)
2 .O slashed.H, 1 liter
Colourless 50 mgs.
crystallised on evap.sup.n.
m.p. 89-90.degree.; (cunaniol)
cunaniol-type U.V.
3 CHCl.sub.3
Yellow solution 134 mgs.
brown syrup on evap.sup.n.
cunaniol-type U.V.
mol. wt. 426; (cunaniol-
glycoside)
IR: 2220 cm.sup.-1 (C .tbd. C),
1740 cm.sup.-1 (ester)
4 ethanol dark brown solution
10 mgs.
(discarded)
______________________________________
The glycoside provides a soluble form of cunaniol which is readily
liberated on hydrolysis of the glycoside link.
Administration Examples
The compounds may be administered orally, topically, parenterally
(subcutaneously, intramuscularly, intravenously), enterally, rectally,
vaginally or by any other appropriate route. They may be made up into
tablets, hard or soft gel capsules, pastilles, emulsions, enteral or
parenteral formulae, foams, ointments, creams, lotions, suppositories,
pessaries or any other appropriate form known to those skilled in the art.
They may be made up into pharmaceutical dosage forms, or into foods which
have a specific medical or health-related purpose.
It will be understood that the absolute quantity of active materials
present in any dosage unit should not exceed that appropriate to the rate
and manner of administration to be employed but on the other hand should
also desirably be adequate to allow the desired rate of administration to
be achieved by a small number of doses. The rate of administration will
moreover depend on the precise pharmacological action desired. For
example, the dosage amounts will be dependent on whether the use is for
targeting the whole body or specific tissue (e.g. heart
blocking/restarting) or whether the compounds are being used as an
analeptic.
The dosage units may suitably be prepared so as to deliver from 1 microg.
to 10 g, preferably from 500 microg to 1 g and very preferably from 1 mg
to 50 mg of the cunaniol or cunaniol derivative per kg body weight.
The dosage units may contain concentrations of 0.1 microg to 100 mg/ml,
preferably 1 microg to 1 mg/ml and very preferably 10 microg to 100
microg/ml of the cunaniol or cunaniol derivative.
When prepared for topical administration or in enteral or parenteral
formulations or food they may be made in the formulae containing from
0.01% to 60% by weight of the final formulation, preferably from 0.1% to
30% by weight, and very preferably from 1% to 10% by weight.
The preparations may be used in any disease condition likely to respond to
the cunaniol or cunaniol derivative.
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